Powder-layered oral dosage forms

ABSTRACT

An oral dosage form of morphine is formulated by powder-layering an homogeneous mixture of morphine sulfate and hydrous lactose impalpable onto inert beads to obtain a multiparticulate product. A plurality of the powder-layered beads may be administered either in immediate release form or in an extended release form by coating with a hydrophobic material. In addition, multi-particulate oral dosage forms containing therapeutically effective agents containing a plurality of pharmaceutically acceptable inert beads powder-layered with homogeneous mixture of a therapeutically effective agent and hydrous lactose impalpable are also disclosed. A method of preparing the dosage forms as well as a method preparing spheroids containing the homogeneous mixture of therapeutically effective agent and hydrous lactose impalpable are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 09/005,864, filed Jan. 12, 1998 now U.S. Pat. No. 6,077,533,which is a continuation-in-part of U.S. patent application Ser. No.08/760,724, filed on Dec. 5, 1996 now abandoned, which in turn is acontinuation of U.S. patent application Ser. No. 08/431,359, filed onApr. 28, 1995 now abandoned, which in turn is a continuation-in-part ofU.S. patent application Ser. No. 08/249,150, filed on May 25, 1994, nowU.S. Pat. No. 5,411,745, the disclosures of which are all herebyincorporated by reference.

BACKGROUND OF THE INVENTION

One method of obtaining pharmaceutical products involves the use of aninert spherical bead which is coated with a drug in powder form. Thistechnique, referred to in the art as “powder layering”, generallyinvolves the surface of the beads being coated with a binder solution,with the drug being applied onto the beads in powder form. Thistechnique is usually suitable for the preparation of a wide range ofdrugs in immediate release form.

Powder layering techniques are well-known in the art, and are generallyconsidered to work best with drugs which are freely soluble in water.Such drugs may be powder-layered directly onto the surface of tackyinert beads alone, or with additional excipients. In certain instances,it is preferable to use a spheronizing agent to add in the processing(layering) of the drug onto the beads. This is the case when the drug tobe powder-layered is not freely water soluble.

U.S. Pat. No. 2,738,303 describes a sympathomimetic preparation whichconsists of small pellets coated with various thicknesses of a materialslowly digestible or dispersible in the gastrointestinal tract. Thesepellets are prepared by placing small sugar pellets (non-pareil seeds)from 12–40 mesh in a rotating coating pan, wetting the sugar pelletsusing syrup U.S.P. or gelatin, and then coating them with a powder ofthe sympathomimetic. Thereafter, the powder-coated pellets are said tobe extended by coating with a wax-fat coating such as a mixture ofglyceryl monostearate and beeswax. In each of the examples, thenon-pareil seeds were powder-layered to a low load (e.g., less than 50%of the total weight of the powder-layered pellet).

U.S. Pat. No. 5,026,560, which describes a method for producingpowder-layered granules which are said to be spherical and which aresaid to be suitable for the application of a further coating forcontrolled release. Therein, granules are prepared by coating seed coreswith a spraying powder contained a drug and a low substitutedhydroxypropylcellulose powder, while at the same time spraying the seedcores with an aqueous binder. The powder contains 5–90 percent by weightof the low substituted hydroxypropylcellulose (preferably 10–60 percent)and 2–70 percent by weight of drug (preferably 5–50 percent). The ratioof the aqueous binder to powder is said to be 1:1–1:2. The granulesthereby produced are said to be spherical and to have an excellenthardness and disintegration.

WO 93/07861 describes multiphase microspheres containing a molecularcompound dispersed in a polymeric matrix which are said to achieve drugloading efficiencies between 80 and 100 percent. Particular ratios ofwater/oil emulsion to polymer and concentration of surfactant anddispersion media such as mineral oil is used to provide the beneficialresult.

The use of organic solvents in the preparation of pharmaceuticalformulations is considered undesirable because of inherent problems withregard to flammability, carcinogenicity, environmental concerns, cost,and safety in general. Therefore, it would be desirable to manufacturean immediate release morphine sulfate product or other therapeuticallyeffective agent-containing product without the use of such organicsolvents.

Many of the oral opioid analgesic formulations that are currentlyavailable in the market must be administered every four to six hoursdaily with a selected few formulated for less frequent 12 hour dosing.There is a need in the art to develop drug formulations which provide aduration of effect lasting longer than twelve hours such as a drug thatmay be administered to a patient only once a day. Morphine, which isconsidered to be the prototypic opioid analgesic, has been formulatedinto 12 hour controlled-release formulations (i.e., MS Conting tablets,commercially available from Purdue Frederick Company).

An orally administrable morphine formulation which would provide anextended duration of effect would be highly desirable. Such an oralsustained-release formulation of an opioid analgesic would provideeffective steady-state blood levels (e.g., plasma levels) of the drugwhen orally administered such that a duration of effect greater than 12hours, and more preferably, of about 24 hours or more, which formulationis fully bioavailable as well.

It would also be highly desirable to provide similarorally-administrable formulations containing therapeutically effectiveagents other than morphine.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide a method forproviding a high-load immediate release multiparticulate formulation ofmorphine for oral administration.

It is another object of the present invention to an immediate releasemorphine sulfate multiparticulate oral dosage form which comprisespowder-layered spheroids which are bioavailable which avoid thenecessity for using organic solvents in the manufacture of themultiparticulate dosage form.

It is another object of the present invention to produce an immediaterelease dosage form of morphine which is bioequivalent and minimizes thefood effect.

It is a further object of the present invention to provide an orallyadministered pharmaceutical dosage form of morphine that is suitable foronce-a-day administration, which dosage form is bioavailable.

It is another object of the present invention to provide extendedrelease formulations of drugs which are administered in relatively largeamounts, in particular morphine, which formulations comprisepowder-layered spheres which have been coated with a material suitablefor providing the desired release rate of the drug.

It is a further object of the present invention to provide a method forproviding extended release high-load powder-layered spheroidformulations of morphine.

It is an object of the present invention to provide a method forpreparing high-load immediate release multiparticulate formulationscontaining therapeutically effective agents for oral administration.

It is another object of the present invention to provide an immediaterelease multiparticulate oral dosage form which comprises spheroidspowder-layered with a therapeutically effective agent which isbioavailable and which avoids the necessity for using organic solventsin the manufacture thereof.

It is another object of the present invention to produce an immediaterelease dosage form of a therapeutically effective agent which isbioavailable and minimizes the food effect.

It is a further object of the present invention to provide an orallyadministered pharmaceutical dosage form of a therapeutically effectiveagent that is suitable for once-a-day administration, which dosage formis bioavailable.

It is another object of the present invention to provide extendedrelease formulations of drugs which are administered in relatively largeamounts in the form of powder-layered spheres which have been coatedwith a material suitable for providing the desired release rate of thedrug.

The above objects and others are accomplished by the present invention,which relates in part to oral dosage forms comprising inertpharmaceutical beads which are powder-layered with a therapeuticallyeffective agent. In certain preferred embodiments, the therapeuticallyeffective agent is powder-layered onto the inert pharmaceutical beadsuntil they attain a weight gain of greater than about 50%.

The present invention therefore is directed in part to the surprisingdiscovery that in order to powder-layer certain therapeuticallyeffective agents onto inert pharmaceutical beads, it is necessary toutilize a processing aid consisting essentially of hydrous lactoseimpalpable. The hydrous lactose impalpable is intimately admixed withthe therapeutically effective agent prior to layering thetherapeutically effective agent onto the inert pharmaceutical beads. Thetherapeutically effective agents included in the formulations of thepresent invention have a bulk density of from about 0.2 to about 0.8g/ml and preferably from about 0.4 to about 0.75 g/ml. The hydrouslactose impalpable has a bulk density of from about 0.4 to about 0.9g/ml and preferably from about 0.5 to about 0.7 g/ml.

The invention further relates to a method of preparing bioavailable oraldosage forms containing inert beads powder-layered with atherapeutically effective agent. The method includes determining thebulk density of the therapeutically effective agent, admixing thetherapeutic agent with a pharmaceutically acceptable inert diluenthaving a bulk density of from about 75% to about 125% of the therapeuticagent bulk density to form a homogeneous mixture; spraying an aqueousbinder solution onto inert beads having a diameter from about 0.1 mm toabout 3.0 mm, to provide the beads with a tacky surface; powder layeringthe homogeneous mixture of therapeutically effective agent and thediluent onto the beads once the beads have become tacky, to a weightgain of at least about 50%; drying the coated beads to obtainpowder-layered beads having a smooth surface; and sieving thepowder-layered beads to obtain a powder-layered multiparticulate producthaving a suitable range of particle size. Preferably thepharmaceutically acceptable inert diluent is not water swellable.

The invention further relates to a method of preparing bioavailable oraldosage forms containing inert beads powder-layered with atherapeutically effective agent. The method includes determining thebulk density of the therapeutically effective agent, admixing thetherapeutic agent with a pharmaceutically acceptable inert diluentcomprising hydrous lactose impalpable powder having a bulk density offrom about 75% to about 125% of the therapeutic agent's to form ahomogeneous mixture; spraying an aqueous binder solution onto inertbeads having a diameter from about 0.1 mm to about 3.0 mm, to providethe beads with a tacky surface; powder layering the homogeneous mixtureof therapeutically effective agent and the diluent onto the beads oncethe beads have become tacky, to a weight gain of at least about 50%;drying the coated beads to obtain powder-layered beads having a smoothsurface; and sieving the powder-layered beads to obtain a powder-layeredmultiparticulate product having a suitable range of particle size.

The invention further relates to a method of treating a mammal with anoral formulation containing a therapeutic agent. The method includespreparing a powder-layered multiparticulate formulation oftherapeutically effective agent as set forth above, incorporating aplurality of the beads into unit doses each having a desired quantity oftherapeutically effective agent, and orally administering the unit doseto a patient in need thereof. When orally administered, the unit dose ofimmediate release therapeutically effective agent provides effectiveblood plasma levels of therapeutically effective agent for about 4hours, and the unit dose of extended release therapeutically effectiveagent provides effective blood plasma levels of therapeuticallyeffective agent for about 12–24 hours.

The present invention is further related to a bioavailable extendedrelease therapeutically effective agent dosage form for once-a-day oraladministration. The dosage form comprises inert pharmaceuticallyacceptable beads having a diameter from about 0.1 mm to about 3 mm whichhave been powder-layered with therapeutically effective agent, andthereafter coated to a desired weight gain with a hydrophobic materialto obtain the desired extended release of the drug when the formulationis exposed to fluids.

The above objects and others are accomplished by the present invention,which relates in part to oral dosage forms comprising inertpharmaceutical beads which are powder-layered with morphine sulfate. Theresultant multiparticulate formulation is manufactured without the useof organic solvents.

In certain preferred embodiments, the morphine is powder-layered ontothe inert pharmaceutical beads until they attain a weight gain ofgreater than about 50%.

The present invention therefore is directed in part to the surprisingdiscovery that in order to powder-layer morphine sulfate onto inertpharmaceutical beads, it is necessary to utilize a processing aidconsisting essentially of hydrous lactose impalpable. The hydrouslactose impalpable is intimately admixed with the morphine sulfate priorto layering the morphine sulfate onto the inert pharmaceutical beads.

The invention further relates to a method for preparing bioavailable,immediate release powder-layered beads of morphine sulfate suitable fororal administration comprising spraying an aqueous binder solution ontoinert beads having a diameter from about 0.1 mm to about 3.0 mm, toprovide said beads with a tacky surface; spraying a powder consisting ofa homogeneous mixture of morphine sulfate and hydrous lactose impalpablepowder onto the beads once the beads have become tacky, to a weight gainof at least about 50%; drying said coated beads to obtain powder-layeredbeads having a smooth surface suitable; and sieving the powder-layeredbeads to obtain a powder-layered multiparticulate product having asuitable range of particle size. The invention further relates to amethod of treating a patient for moderate to severe pain with abioavailable immediate release opioid analgesic oral dosage form,comprising preparing a powder-layered multiparticulate formulation ofmorphine sulfate as set forth above, dividing the multiparticulateproduct into unit doses each having a desired quantity of morphinesulfate, and administering the unit dose to a patient suffering frommoderate to severe pain. When orally administered, the unit dose ofimmediate release morphine sulfate provides effective blood plasmalevels of morphine for about 4 hours, and the unit dose of extendedrelease morphine sulfate provides effective blood plasma levels ofmorphine for about 12–24 hours.

The present invention is further related to a bioavailable extendedrelease morphine dosage form for once-a-day oral administration. Thedosage form comprises inert pharmaceutically acceptable beads having adiameter from about 0.1 mm to about 3 mm which have been powder-layeredwith morphine, and thereafter coated to a desired weight gain with ahydrophobic material to obtain the desired extended release of the drugwhen the formulation is exposed to fluids.

The hydrophobic material is selected from the group consisting of (i) anacrylic polymer such as copolymers of acrylic and methacrylic acid; (ii)an alkylcellulose such as ethylcellulose; (iii) other commonly usedretardant coatings such as shellac, zein, and hydrophobic wax orwaxy-type products either alone or in admixture with fatty (aliphatic)alcohols (e.g., cetostearyl alcohol), hydrogenated castor oil, orhydrogenated vegetable oil, or (iv) mixtures of any of groups (i)–(iii).The extended release oral dosage form provides the desired analgesiceffect when administered, e.g., to a human patient, for at least about24 hours.

For purposes of the present invention, the terms “bead” is meant toencompass any inert substrate having a size from about 0.1 mm to about3.0 mm, and is deemed to encompass inert spheres, seeds, pellets,spheroids, cores, granules, particles, a compressed tablet made fromthese “beads”, and the like.

The term “unit dose” is defined for purposes of the present invention asthe total amount of beads needed to administer a desired dose of drug(e.g., morphine sulfate or a therapeutically effective agent) to apatient. For purposes of the present invention, the term“therapeutically effective agent” is meant to encompass anypharmaceutically acceptance compound or composition and/or medicinalsubstance which can be administered to achieve a treatment effect inmammals. For example and without limitation, therapeutically effectiveagents include analgesics such as acetaminophen, gastrointestinal agentssuch as metaclopramide, narcotic analgesics such as codeine phosphateUSP Special powder, codeine phosphate USP powder, codeine sulfate USPMedium crystals-fine and tramadol, bronchodilating agents such astheophylline anhydrous and aminophylline USP, non-steroidalanti-inflammatory agents such as diclofenac sodium, antibioticsubstances such as doxycycline metaphosphate sodium complex and vitaminproducts such as sodium ascorbate.

For purposes of the present invention, the term “environment of use” ismeant to encompass an in-vitro testing apparatus, or an in-vivolocation, such as the gastrointestinal tract.

The term “high-load” is defined for purposes of the present invention asencompassing any powder-layered beads which have a drug content of about50% or more, by weight.

The term “low-load” is defined for the purposes of the present inventionas encompassing any powder-layered beads which have a drug content ofless than about 50%, by weight.

The term “bioavailable” is defined for the purposes of the presentinvention as the total amount of a drug substance that is absorbed to beavailable to provide the desired therapeutic effect after administrationof a unit dosage form, as compared to the known reference drug product,as commonly determined and accepted by Governmental Regulatory Agencies,such as the United States FDA.

The term “bioavailability” is defined for purposes of the presentinvention as the extent to which the drug (e.g., opioid analgesic) isabsorbed from the unit dosage forms and becomes available at the site ofdrug action.

The term “immediate release” is defined for purposes of the presentinvention as the release of the drug (e.g., opioid analgesic) at such arate that blood (e.g., plasma) levels are maintained within thetherapeutic range but below toxic levels over a period of time of about4 hours.

The term “extended release” is defined for purposes of the presentinvention as the release of the drug (e.g., opioid analgesic) at such arate that blood (e.g., plasma) levels are maintained within thetherapeutic range but below toxic levels over a period of time of about12–24 hours or longer.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawing is illustrative of embodiments of the inventionand is not meant to limit the scope of the invention as encompassed bythe claims.

FIG. 1 is a graph depicting the blood level plasma of Example 1 bothfasted and fed as compared to reference standard.

FIG. 2 is a graph depicting the blood plasma levels obtained with theformulation of Examples 4 and 5.

FIG. 3 is a graph depicting the blood plasma levels obtained with theformulation of Example 10, both fasted and fed, as compared to areference standard.

DETAILED DESCRIPTION

The inert beads which may be powder-layered in accordance with thepresent invention include commercially available nonpareils and seedcores. Suitable cores include Sugar Spheres, NF. Inert beads having asize from about 30/35 to about 14/16 μmay be used. Generally, the sizeof the beads is from about 0.1 mm to about 2.5 mm.

The binder which is used in the present invention may be anypharmaceutically acceptable binder known to those skilled in the art.Such binders include, for example, polyvinylpyrrolidone, natural andsynthetic gums including gum arabic, hydroxypropyhnethylcellulose,hydroxypropylcellulose, carboxymethylcellulose, methylcellulose,pullulan, dextrin, starch, and the like. The binder may be dissolved ordispersed in an aqueous or organic solution, or a mixture thereof.Aqueous binder solutions or dispersions are especially preferred.Suitable binding agents which are generally considered to bewater-soluble include polyvinylpyrrolidone,hydroxypropylmethylcellulose, and maize starch. Many other water-solublebinding agents which would be suitable for use in conjunction with thepresent invention are known to those skilled in the art. In onepreferred embodiment, an aqueous 5% polyvinylpyrrolidone solution isutilized as the binder solution.

The spraying powder comprising the drug may also include additionalinert excipients, including glidants, diluents, stabilizers, coloringagents, and binders. Suitable glidants include, e.g., colloidal silicondioxide and/or talc. Suitable diluents include, e.g., polysaccharides,monosaccharides, corn starch, and the like.

The morphine which is included in the formulations of the presentinvention is preferably included as the sulfate salt. Chemically,morphine sulfate is an opioid analgesic having the structure 7,8didehydro-,5 α-epoxy-17-methylmorphinan-3,6 α-diol sulfate (2:1) saltpentahydrate.

In the immediate release formulations of the present invention, it ispreferred that the unit dose contains from about 5 mg to about 60 mg ofmorphine (provided either as morphine base or a pharmaceuticallyacceptable morphine salt, such as morphine sulfate). In most preferredembodiments, the unit dose contains either 15 mg, 20 mg, or 30 mg,morphine (based on the sulfate salt thereof).

In the sustained release embodiment of the present invention, the unitdose contains from about 5 mg to about 800 mg morphine (provided as thesulfate salt), by weight.

Due to size constrictions for an oral dosage form, it is desirable incertain formulations of the present invention to provide the sphereswith a high load of drug. In the high-load formulations of the presentinvention, the spheres comprise 50% or more drug, by weight. In certainpreferred embodiments, the spheres comprise 70% or more drug, by weight.

It has been found by the inventors that morphine sulfate is not readilypowder-layered onto the surface of inert pharmaceutical beads, thesurfaces of which have been made tacky via the use of a binder. It ispostulated that this is due in part to the fact that while morphinesulfate is soluble in water (16–24 grams in one liter of water),morphine sulfate is not freely soluble in water.

It has also been found by the inventors that certain therapeuticallyeffective agents are not readily powder-layered onto the surface ofinert pharmaceutical beads, the surfaces of which have been made tackyvia the use of a binder. It is postulated that this is due in part tothe fact that while these therapeutically effective agents may besomewhat soluble in water, they are not freely soluble in water. Even ifthe selected therapeutically effective agent is sufficiently watersoluble, it would be desirable to have an alternative means forpowder-layering available to the artisan.

Especially in the case of low-load morphine beads for immediate releaseformulations, due to the low dose of morphine a diluent is needed inorder to properly (uniformly) distribute the morphine on the beads. Thiswould also be the case for other low-load therapeutically effectiveagent beads prepared for immediate release formulations.

It is recognized among those skilled in the art that in cases where thedrug to be powder-layered is not freely water soluble, such drugs maynot be good candidates for powder-layering techniques, and it is oftennecessary to include an excipient which has an amorphous physicalstructure and which is highly water soluble in order to obtain anacceptable product. Morphine sulfate has been found to be such a drug.Other therapeutically effective agents, some of which are also notfreely soluble have also been found to be candidates for powderlayering.

To date, the practice has been to use a spheronizing agent,microcrystalline cellulose, mixed with the drug inextrusion/spheronization techniques. However, microcrystalline cellulosecannot be utilized in powder-layering techniques because it swells.Other typically used processing aids such as spray-dried lactose alsohave been found not to provide an acceptable product.

The processing aid, “lactose” is generally defined to mean lactose NF,which encompasses anhydrous lactose and lactose monohydrate. Thisdefinition is supported by the U.S. Pharmacopeia 23/National Formulary18, 1995, hereby incorporated by reference, which lists only these twomonographs under the lactose heading. There are many other grades oflactose which are commercially available to those skilled in the art.Each of these grades have different particle size and differentproperties, as demonstrated by the Handbook of PharmaceuticalExcipients, published by the American Pharmaceutical Association 1986,hereby incorporated by reference. Accordingly, the differentcommercially available grades of lactose are used in differentsituations during the manufacturing of pharmaceutical formulations andare not interchangeable for purposes of the present invention, e.g., asa processing aid in powder-layering applications.

For example, spray-dried lactose, generally considered to be theexcipient of choice as a bulking agent in dry granulations because ofits excellent flow properties, does not act as an effective processingaid in the powder-layering methods and formulations of the presentinvention. It has been found that the powder-layered beads obtainedthrough the use of spray-dried lactose as the processing aid topowder-layer pharmaceutically acceptable inert beads with a drug havinga bulk density within the claimed range of 0.2 to 0.8 g/ml produced aproduct which was irregular in shape which would not lend itself to beencapsulated. Nor would this irregular shape lend itself to beingfilm-coated in a uniform manner, with respect to achieving a uniformthickness of functional film around the substrate. Further, due to theirregularity of the shape, the powder-layered beads have a high angle ofrepose, and therefore provide poor filling characteristics on aconventional capsule filling machine. This would result in unacceptablefluctuations in the weight of the final encapsulated product.

In sharp contrast to spray dried lactose, hydrous lactose impalpablepossesses poor flow characteristics and is therefore not considereduseful in dry granulations. However, it is useful in the preparation ofpharmaceutical wet granulations because of its fine particle size (henceits ability to blend well with drug substances and form a granule).

It has now been surprisingly discovered that by choosing a processingaid having a bulk density similar to that of morphine sulfate or that ofother therapeutically effective agents, an pharmaceutically acceptable,bioavailable product can be obtained using powder-layering techniques.More particularly, it has been discovered that excellent results areobtained utilizing hydrous lactose impalpable as a processing aid.Hydrous lactose impalpable is commercially available, for example, fromB.V. Hollandsche Melksuiker-fabriek (HMS), Uitgeest, Holland. Typically,the hydrous lactose impalpable which is suitable for use in the presentinvention has a poured and tapped bulk density from about 0.4 to about0.9 g/ml, and more preferably from about 0.5 g/ml to about 0.7 g/ml.Hydrous lactose impalpable is highly water soluble and has beendiscovered to readily layer onto the surface of tacky beads. Theresultant product has a smooth, regular surface which provides theformulation with excellent filling characteristics, acceptable weightfluctuations in the weight of the final encapsulated product, and asurface which can be readily film-coated. The present invention alsocontemplates the inclusion of other inert pharmaceutically acceptablediluents in addition to or as alternatives to hydrous lactoseimpalpable. In this regard, the inert pharmaceutically acceptablediluents will have a bulk density of from about 75 to about 125% of thatof the therapeutically effective agent. Further, the pharmaceuticallyacceptable diluent should be preferably not water swellable. Anon-limiting list of examples of processing aids meeting this criteriaincludes hydrous lactose impalpable, maltodextrin, povidone (K30),pregelantized corn starch, confectioner's sugar, and talc (100%). Thislist provided is not meant to be exclusive. Many other processing aidswould be obvious to those skilled in the art, and are contemplated to bewithin the scope of the appended claims. It is to be understood,however, that hydrous lactose impalpable is the preferred diluent.

In preferred embodiments, the morphine sulfate has a bulk density(poured and tapped) from about 0.2 g/ml to about 0.7 g/ml, morepreferably from about 0.4 g/ml to about 0.5 g/ml, and is homogeneouslymixed with hydrous lactose impalpable prior to powder layering themixture onto the beads. In further embodiments, the therapeuticallyeffective agents have a bulk density (poured and tapped) from about 0.2g/ml to about 0.8 g/ml, more preferably from about 0.4 g/ml to about0.75 g/ml, and is homogeneously mixed with hydrous lactose impalpableprior to powder layering the mixture onto the beads. A non-limiting listof therapeutically effective agents meeting this criteria is set forthbelow:

Tapped Bulk Densities (g/ml) Acetaminophen  035–0.46 Metoclopramide HCL0.5  Codeine Phosphate USP Special Powder 0.55 Codeine Phosphate USPPowder 0.25 Codeine Sulfate USP Medium 0.7–0.5 Crystals Fine DoxycyclineMetaphosphate Sodium 0.49 Complex Tramadol HCL* 0.42 TheophyllineAnhydrous* 0.44 Aminophylline USP* 0.62 Diclofenac Sodium* 0.31 SodiumAscorbate USP* 0.66 *Bulk Densities performed at PRC

In preferred embodiments, the homogeneous powder mixture consistsessentially of morphine sulfate or other therapeutically effective agentand hydrous lactose impalpable in a ratio from about 98:2 to about 2:98.Most preferably, the ratio of morphine sulfate or other therapeuticallyeffective agent to hydrous lactose impalpable is from about 60:40 toabout 40:60

Although hydrous lactose impalpable is a known excipient to thoseskilled in the art, its previous known use was limited to use as abulking agent or diluent in pharmaceutical dosage forms.

The homogeneous powder mixture can further include minor amounts ofother pharmaceutically acceptable processing aids such as solublediluents such as maltodextrin, sucrose, starches, certain grades ofhydrophilic cellulose polymers, insoluble diluents such as talc,dicalcium phosphate and certain of hydrophobic cellulose polymers.

The powder-layered spheres of the invention may be prepared as follows.The drug together with any pharmaceutically necessary excipients (e.g.,a glidant such as colloidal silicon dioxide) are mixed together. Priorto powder layering, a suitable binder solution (e.g., a 5% PVP aqueoussolution) or cellulose solution or acrylic polymers, gums, etc., isprepared. The inert substrate (e.g., sugar spheres) are placed in, e.g.,a Glatt rotor processor, and the binder solution is sprayed whenoperating conditions are attained. Once the sugar spheres (beads) aretacky, the powder comprising the drug is fed into the rotor processor.As the powder begins to layer on beads, both binder solution spray rateand powder feed rate are increased. Spray rate and powder feed rateproportions may be determined, e.g., by examining the tackiness beadsduring processing. The binder solution is continued to be sprayed ontothe beads after all powder has been layered, to protect beads duringdrying. The powder-layered beads are then dried to a suitable loss ondrying (LOD), for example to a moisture content of approximately 6%. Thelayered beads are then passed through a series of screens to removeundesirable sized beads. For example, in certain embodiments, thescreens may remove that portion of the beads having diameters above 1.19mm and below 0.84 mm.

The device which is utilized for powder-layering the beads is known tothose skilled in the art. Such a device is described in detail in U.S.Pat. No. 5,132,142, hereby incorporated by reference.

The ratio of the powder feed rate to the solution feed rate is may befrom about 1:10 to about 10:1, and more preferably from about 2:1 toabout 1:1, at room temperature.

In preferred embodiments of the invention directed to immediate releasepowder-layered beads comprising a therapeutically effective agent, theformulation preferably provides an in-vitro dissolution rate for animmediate release (4-hour) dosage form, when measured by the USP PaddleMethod at 100 rpm in 900 ml aqueous buffer, at 37° C. between 70 and100% (by wt) drug released after 1 hour. USP Paddle Method is the PaddleMethod described, e.g., in U.S. Pharmacopoeia XXII (1990). The dosageform preferably provides a peak plasma level of the opioid in-vivo fromabout 0.25 to about 4 hours after oral administration.

In embodiments of the present invention directed to extended releaseformulations, the powder-layered beads which are suitable for use as animmediate release product are coated with a extended release coating.The coating formulations of the present invention should be capable ofproducing a strong, continuous film that is smooth and elegant, capableof supporting pigments and other coating additives, non-toxic, inert,and tack-free.

The extended release formulations of the present invention provide adissolution rate in-vitro of the dosage form, when measured by the USPPaddle Method at 100 rpm in 900 ml aqueous buffer, pH between about 1.6and about 7.2 at 37° C., of from about 0 to about 40% (by wt) releasedafter one hour, from about 5 to about 60 percent (by wt) released after2 hours, from about 11 to about 70% (by wt) released after 4 hours, fromabout 15 to about 80% (by wt) released after 8 hours, from about 25 toabut 85% (by wt) released after 12 hours), and greater than 65% (by wt)released after 24 hours, the dosage form providing a duration of effectin-vivo for at least about 24 hours.

In a preferred embodiment, the extended release dosage forms provide adissolution rate in-vitro of the dosage form, when measured by the USPPaddle Method at 100 rpm in 900 ml aqueous buffer, pH between about 1.6and about 7.2 at 37° C., of from about 0 to about 20% (by wt) releasedafter one hour, from about 10 to about 40 percent (by wt) released after2 hours, from about 20 to about 70% (by wt) released after 4 hours, fromabout 50 to about 80% (by wt) released after 8 hours, from about 60 toabut 90% (by wt) released after 12 hours), and greater than 70% (by wt)released after 24 hours, the dosage form providing a duration of effectin-vitro for at least about 24 hours.

In order to obtain an extended release of the morphine sufficient toprovide an analgesic effect for the desired duration of effect, thepowder-layered beads may be coated with a sufficient amount of acontrolled release agent such as a hydrophilic or a hydrophobic materialto a weight gain level from about 2 to about 30 percent, although theovercoat may be greater depending upon the particular ingredientsutilized in the coating, and the desired release rate, among otherthings. Extended release of other therapeutically effective agentssufficient to provide a desired duration of effect is carried out in asimilar manner.

The solvent which is used for the controlled release material may be anypharmaceutically acceptable solvent, including water, methanol, ethanol,methylene chloride and mixtures thereof. It is preferable however, thatthe coatings be based upon aqueous dispersions of the hydrophobicmaterial.

In certain preferred embodiments of the present invention, hydrophobicpolymers such as the sustained-release coating comprise apharmaceutically acceptable acrylic polymer, including but not limitedto acrylic acid and methacrylic acid copolymers, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cynao-ethyl methacrylate,aminoalkyl methacrylate copolymer, poly(acrylic acid), polymethacrylicacid, methacrylic acid alkylamide copolymer, poly(methyl methacrylate),poly(methacrylic acid anhydride), methyl methacrylate, polymethacrylate,polyacrylamide and glycidyl methacrylate copolymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers. Ammonio methacrylatecopolymers are well known in the art, and are described in NF XVII asfully polymerized copolymers of acrylic and methacrylic acid esters witha low content of quaternary ammonium groups.

In one preferred embodiment, the acrylic coating is an acrylic resinlacquers used in the form of an aqueous dispersion, such as that whichis commercially available from Rohm Pharma under the TradenameEudragit®. In further preferred embodiments, the acrylic coatingcomprises a mixture of two acrylic resin lacquers commercially availablefrom Rohm Pharma under the Tradenames Eudragit® RL 30 D and Eudragit® RS30 D, respectively. Eudragit® RL 30 D and Eudragit® RS 30 D arecopolymers of acrylic and methacrylic esters with a low content ofquaternary ammonium groups, the molar ratio of ammonium groups to theremaining neutral (meth)acrylic esters being 1:20 in Eudragit® RL 30 Dand 1:40 in Eudragitg RS 30 D. The mean molecular weight is about150,000. The code designations RL (high permeability) and RS (lowpermeability) refer to the permeability properties of these agents.Eudragit® RL/RS mixtures are insoluble in water and in digestive fluids.However, coatings formed from the same are swellable and permeable inaqueous solutions and digestive fluids.

The Eudragit® RL/RS dispersions of the present invention may be mixedtogether in any desired ratio in order to ultimately obtain asustained-release formulation having a desirable dissolution profile.Desirable sustained-release formulations may be obtained, for instance,from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit®RL and 50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Ofcourse, one skilled in the art will recognize that other acrylicpolymers may also be used, such as, for example, Eudragit® L.

In other preferred embodiments, the hydrophobic polymer which may beused for coating the substrates of the present invention is ahydrophobic cellulosic material such as ethylcellulose. Those skilled inthe art will appreciate that other cellulosic polymers, including otheralkyl cellulosic polymers, may be substituted for part or all of theethylcellulose included in the hydrophobic polymer coatings of thepresent invention.

One commercially-available aqueous dispersion of ethylcellulose isAquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is preparedby dissolving the ethylcellulose in a water-immiscible organic solventand then emulsifying the same in water in the presence of a surfactantand a stabilizer. After homogenization to generate submicron droplets,the organic solvent is evaporated under vacuum to form a pseudolatex.The plasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, it isnecessary to intimately mix the Aquacoat® with a suitable plasticizerprior to use.

Another aqueous dispersion of ethylcellulose is commercially availableas Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product isprepared by incorporating plasticizer into the dispersion during themanufacturing process. A hot melt of a polymer, plasticizer (dibutylsebacate), and stabilizer (oleic acid) is prepared as a homogeneousmixture, which is then diluted with an alkaline solution to obtain anaqueous dispersion which can be applied directly onto substrates.

In embodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic polymer, the inclusion of aneffective amount of a plasticizer in the aqueous dispersion ofhydrophobic polymer will further improve the physical properties of thefilm. For example, because ethylcellulose has a relatively high glasstransition temperature and does not form flexible films under normalcoating conditions, it is necessary to plasticize the ethylcellulosebefore using the same as a coating material. Generally, the amount ofplasticizer included in a coating solution is based on the concentrationof the film-former, e.g., most often from about 1 to about 50 percent byweight of the film-former. Concentration of the plasticizer, however,can only be properly determined after careful experimentation with theparticular coating solution and method of application.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, acetyl triethyl citrate, tributyl citrate, andtriacetin, although it is possible that other water-insolubleplasticizers (such as acetylated monoglycerides, phthalate esters,castor oil, etc.) may be used. Triethyl citrate is especially preferred.

Examples of suitable plasticizers for the acrylic polymers of thepresent invention include citric acid esters such as triethyl citrate NFXVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propyleneglycol, polyethylene glycols, propylene glycol, diethyl phthalate,castor oil, and triacetin, although it is possible that otherwater-insoluble plasticizers (such as acetylated monoglycerides,phthalate esters, castor oil, etc.) may be used. Triethyl citrate isespecially preferred.

The dissolution profile of the extended release formulations of theinvention can be altered, for example, by varying the thickness of thehydrophobic coating, changing the particular hydrophobic material used,or altering the relative amounts of, e.g., different acrylic resinlacquers, altering the manner in which the plasticizer is added (e.g.,when the sustained-release coating is derived from an aqueous dispersionof hydrophobic polymer), by varying the amount of plasticizer relativeto hydrophobic polymer, by the inclusion of additional ingredients orexcipients, by altering the method of manufacture, etc.

The plasticized aqueous dispersion of hydrophobic polymer may be appliedonto the powder-layered beads by spraying using any suitable sprayequipment known in the art. In a preferred method, a Wursterfluidized-bed system is used in which an air jet, injected fromunderneath, fluidizes the core material and effects drying while thecoating is sprayed on. A sufficient amount of the aqueous dispersion ofhydrophobic polymer to obtain the desired extended release oftherapeutically effective agent is preferably applied, taking intoaccount the manner of incorporation of the plasticizer, etc. Aftercoating with the hydrophobic polymer, a further overcoat of afilm-former, such as Opadry®, is optionally applied to the beads. Thisovercoat is provided, if at all, in order to substantially reduceagglomeration of the beads.

Next, the coated beads are cured in order to obtain a stabilized releaserate of the therapeutically active agent.

When the coating comprises an aqueous dispersion of ethylcellulose, thecoated substrate is preferably subjected to curing at a temperaturegreater than the glass transition temperature of the coating solution(i.e., ethylcellulose) and at a relative humidity from about 60% toabout 100%, until the curing endpoint is reached, e.g., about 60° C. anda relative humidity from about 60% to about 100% for a time period fromabout 48 to about 72 hours.

In preferred embodiments of the present invention directed to theacrylic coating, a stabilized product is obtained by subjecting thecoated substrate to oven curing at a temperature above the Tg of theplasticized acrylic polymer for the required time period, the optimumvalues for temperature and time for the particular formu-lation beingdetermined experimentally. In certain embodiments of the presentinvention, the stabilized product is obtained via an oven curingconducted at a temperature of about 45° C. for a time period from about24 to about 48 hours or longer.

The release of the therapeutically active agent from thesustained-release formulation of the present invention can be furtherinfluenced, i.e., adjusted to a desired rate, by the addition of one ormore release-modifying agents, or by providing one or more passagewaysthrough the coating. The ratio of hydrophobic polymer to water solublematerial is determined by, among other factors, the release raterequired and the solubility characteristics of the materials selected.

The release-modifying agents which function as pore-formers may beorganic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in the environment of use. Thepore-formers may comprise one or more hydrophilic polymers such ashydroxypropylmethylcellulose. The sustained-release coatings of thepresent invention can also include erosion-promoting agents such asstarch and gums.

The sustained-release coatings of the present invention can also includematerials useful for making microporous lamina in the environment ofuse, such as polycarbonates comprised of linear polyesters of carbonicacid in which carbonate groups reoccur in the polymer chain.

The release-modifying agent may also comprise a semi-permeable polymer.

In other preferred embodiments of the present invention, the sustainedrelease coating comprises hydrophilic polymers, such as cellulose ethersand protein derived materials. Of these polymers, the cellulose ethers,especially hydroxyalkylcelluloses and carboxyalkylcelluloses, arepreferred. Other sustained release coating materials which may be usedin the present invention include digestible, long chain (C₈–C₅₀,especially C₁₂–C₄₀), substituted or unsubstituted hydrocarbons, such asfatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral andvegetable oils and waxes. Hydrocarbons having a melting point of between25° and 90° C. are preferred. Of these long chain hydrocarbon materials,fatty (aliphatic) alcohols are preferred.

Polyalkylene glycols may also be used.

One suitable controlled release coating material comprises at least onewater soluble hydroxyalkyl cellulose, at least one C₁₂–C₃₆, preferablyC₁₄–C₂₂, aliphatic alcohol and, optionally, at least one polyalkyleneglycol. The at least one hydroxyalkyl cellulose is preferably a hydroxy(C₁ to C₆) alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethyl cellulose.The amount of the at least one hydroxyalkyl cellulose in the presentoral dosage form will be determined, inter alia, by the precise rate ofopioid release required. The at least one aliphatic alcohol may be, forexample, lauryl alcohol, myristyl alcohol or stearyl alcohol. Inparticularly preferred embodiments of the present oral dosage form,however, the at least one aliphatic alcohol is cetyl alcohol orcetostearyl alcohol. The amount of the at least one aliphatic alcohol inthe present oral dosage form will be determined, as above, by theprecise rate of opioid release required. It will also depend on whetherat least one polyalkylene glycol is present in or absent from the oraldosage form. In the absence of at least one polyalkylene glycol, theoral dosage form preferably contains between 0.5% and 30% (by wt) of theat least one aliphatic alcohol. When at least one polyalkylene glycol ispresent in the oral dosage form, then the combined weight of the atleast one aliphatic alcohol and the at least one polyalkylene glycolpreferably constitutes between 0.5% and 30% (by wt) of the total dosage.Such coatings may be applied to the powder-layered beads by any knowntechnique utilized by those of ordinary skill in the art.

In one embodiment, the ratio of, e.g., the at least one hydroxyalkylcellulose or acrylic resin to the at least one aliphaticalcohol/polyalkylene glycol determines, to a considerable extent, therelease rate of the opioid from the formulation. A ratio of the at leastone hydroxyalkyl cellulose to the at least one aliphaticalcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred, with aratio of between 1:3 and 1:4 being particularly preferred.

The at least one polyalkylene glycol may be, for example, polypropyleneglycol or, which is preferred, polyethylene glycol. The number averagemolecular weight of the at least one polyalkylene glycol is preferredbetween 1,000 and 15,000 especially between 1,500 and 12,000.

Another suitable controlled-release matrix would comprise analkylcellulose (especially ethyl cellulose), a C₁₂ to C₃₆ aliphaticalcohol and, optionally, a polyalkylene glycol.

In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

The sustained-release coatings of the present invention may also includean exit means comprising at least one passageway, orifice, or the like.The passageway may be formed by such methods as those disclosed in U.S.Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864 (all of whichare hereby incorporated by reference). The passageway can have any shapesuch as round, triangular, square, elliptical, irregular, etc.

In certain embodiments of the present invention, an effective amount ofopioid in immediate release form is included in the unit dose comprisingthe substrates of the present invention. The immediate release form ofthe opioid is included in an amount which is effective to shorten thetime to maximum concentration of the opioid in the blood (e.g., plasma),such that the T_(max) is shortened to a time of, e.g., from about 2 toabout 4 hours. This causes the blood concentration curve to have anearly peak rather than the substantially flattened curves currentlyrecommended by those skilled in the art. It has been discovered that byincluding such an effective amount of immediate release opioid in theunit dose, the experience of relatively higher levels of pain inpatients is significantly reduced. In such embodiments, an effectiveamount of the opioid in immediate release form may be coated onto thesubstrates of the present invention. For example, where the extendedrelease opioid from the formulation is due to a controlled releasecoating, the immediate release layer would be overcoated on top of thecontrolled release coating. On the other hand, the immediate releaselayer may be coated onto the surface of substrates wherein the opioid isincorporated in a controlled release matrix. Where a plurality of thesustained release substrates comprising an effective unit dose of theopioid are incorporated into a hard gelatin capsule, the immediaterelease portion of the opioid dose may be incorporated into the gelatincapsule via inclusion of the sufficient amount of immediate releaseopioid as a powder or granulate within the capsule. Alternatively, thegelatin capsule itself may be coated with an immediate release layer ofthe opioid. One skilled in the art would recognize still otheralternative manners of incorporating the immediate release opioidportion into the unit dose. Such alternatives are deemed to beencompassed by the appended claims.

The multiparticulate unit dose of morphine sulfate or othertherapeutically effective agent may be contained within a hard gelatincapsule. Alternatively, the multiparticulate unit dose of morphinesulfate may be prepared as other dosage forms known to those skilled inthe art, including sachets. The hard gelatin capsule may be opened andthe powder-layered beads containing the drug may be sprinkled intofluids or mixed with food, in particular cool, soft food, such asapplesauce or pudding, or a liquid such as water or orange juice.

In yet a further aspect of the invention, it has been found that all orpart of the microcrystalline cellulose can be eliminated from powderlayer formulations via the use of powder layer promoting agentscomprising hydrous lactose impaplable. In certain preferred embodimentshydrous lactose impalpable comprises all or substantially all of thepowder layer promoting agent. However, other pharmaceuically acceptableinert excipients can be substituted for a portion of the hydrous lactoseimpalpable including but not limited to microcrystalline cellulose. Thusthere is provided an alternative method of making powder layered beadswith reduced amounts or without microcrystalline cellulose. Preferredaspects of this method using hydrous lactose impalpable having a bulkdensity of from about 0.5 to about 0.7 g/ml and therapeuticallyeffective agents having a bulk density of from about 0.4 to about 0.75g/ml.

Another preferred embodiment of the invention is a method for preparingpowder-layered beads containing a therapeutically effective agent,comprising powder-layering inert beads having a diameter from about 0.1mm to about 2.5 mm with a homogeneous powder mixture comprising atherapeutically active agent and a processing aid having a bulk densitywhich is substantially similar to the bulk density of thetherapeutically effective agent, wherein said processing aid is notmicrocrystalline cellulose, until said beads achieve a weight gain of atleast about 10% to about 100%.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

EXAMPLE 1 Immediate Release Low-Load Bead Formulation

In Example 1, low-load morphine sulfate beads were prepared using apowder layering technique in a Glatt Rotor Processor. The beads wereprepared by spraying the aqueous binder solution onto the beads 18/20mesh to provide said beads with a tacky surface. Thereafter, a powderconsisting of a homogeneous mixture of morphine sulfate and hydrouslactose impalpable powder was sprayed onto the beads once the beads havebecome tacky. The beads were then dried and sieved to obtain apowder-layered multiparticulate product having a suitable range ofparticle size. The formula of the morphine sulfate beads is set forth inTable 1 below:

TABLE 1 Amt/Unit Ingredient (mg) Percent (%) Morphine Sulfate Powder 30mg 14.3% Lactose Hydrous Impalpable 42.5 mg 20.2% PVP 2.5 mg  1.2% SugarBeads 18/20 125 mg 59.4% Purified Water qs mg — Opadry Red YS-1-184110.5 mg  4.9% Total 210.5 mg 100.0% 

The lactose hydrous impalpable which is used is obtained from B.V.Hollandsche Melksuiker-fabriek (HMS), Uitgeest, Holland, and containsabout 99.7% lactose monohydrate by weight. Typically, the lactosehydrous impalpable has a bulk density of 0.56 g/ml and a tapped bulkdensity of about 0.64 g/ml. The morphine sulfate has a bulk density ofabout 0.44 g/ml.

Upon completion of the powder-layering, the beads were then filled intogelatin capsules at a 30 mg morphine strength.

The capsules were then subjected to dissolution testing. Dissolutiontesting was conducted on the finished products via USP Apparatus1-(Paddle Method). The capsules were placed into 700 ml of simulatedgastric fluid (without enzymes) for an hour at 100 rpm and 37° C., andit was determined that 90% of the morphine sulfate dissolved within onehour. The dissolution testing indicates that this product would besuitable as an immediate release formulation.

A human single dose bioavailability study was then conducted using theformulation of Example 1 and a reference standard (morphine sulfatesolution, MSIR® solution commercially available from The PurdueFrederick Company), both dosed at 30 mg morphine sulfate per dose. Thereference solution was dosed without food and the test bead product wasdosed without food and with applesauce in a randomized crossover design.The in-vivo results are summarized in Table 2 below, and in FIG. 1.

TABLE 2 Morphine MSIR Sulfate MSIR Capsules Parameter Solution CapsulesWith Food C_(max) (ng/mL)  37.09 (12.60)  34.81 (11.94)  28.63 (10.23)T_(max) (hours)  0.85 (0.54)  1.18 (0.70)  1.36 (0.53) AUC (0, 24)165.34 (35.40) 155.69 (36.09) 145.55 (37.53) (Hr-ng/mL) AUCINF (0, inf)175.38 (36.74) 166.07 (38.33) 156.66 (40.25) (Hr-ng/mL)

This study included a minimal quantity of food (applesauce) and itappears that this product may have the potential of not being affectedby food intake.

EXAMPLE 2 Immediate Release High-Load Bead Formulation

Beads with a high loading of morphine sulfate were produced with the useof a powder layering technique in the Glatt Rotor Processor. The hydrouslactose impalpable was blended with the morphine sulfate prior tomanufacture. The manufacture was otherwise the same as in Example 1. Theformulation of the high load beads is set forth in Table 3 below:

TABLE 3 High Load Beads Percent Ingredient mg/unit (%) Morphine SulfatePentahydrate 30.0 mg 61.73% Powder Lactose Hydrous Impalpable 6.0 mg12.35% Povidone C-30 2.25 mg 5.14% Sugar Beads 30/35 7.75 mg 15.95%Opadry blue YS-1-10542A 2.37 mg 4.83% Purified Water qs — Total 8.6 mg100.0%

Upon completion of the powder-layering, the beads were then filled intogelatin capsules at a 30 mg morphine strength.

The capsules were then subjected to dissolution testing. Dissolutiontesting was conducted on the finished products via USP Apparatus1-(Paddle Method). The capsules were placed into 700 ml of simulatedgastric fluid (without enzymes) for the first hour at 100 rpm and 37°C., and it was determined that 90% of the morphine sulfate dissolvedwithin one hour. The dissolution testing indicates that this productwould be suitable as an immediate release formulation.

EXAMPLE 3 Immediate Release High-Load Bead Formulation

A batch of morphine sulfate high-load beads was manufactured using analternate method of powder layering. The formula is as follows:

TABLE 4 Ingredient mg/unit Morphine Sulfate Powder 50.0 mg LactoseHydrous Impalpable 10.0 mg Povidone 1.5 mg Sugar Beads 30/35 14.0 mgPurified Water qs Opadry Blue YS-1-10542A 3.9 mg Total 79.4 mg

The high-load beads were prepared by first blending the morphine sulfatepowder with the lactose hydrous impalpable. After blending, the Glattrotor processor was charged with the sugar beads and 5 kg of morphinesulfate/lactose blend. The rotor processor was then activated, and thePVP 5% solution was sprayed into the batch. The 5 kg of morphinesulfate/lactose blend is layered without agglomeration occurring. Usingthis procedure, the PVP solution spray rate can be increasedaggressively as compared to the method employed in other methods. Theprocess commenced with first charging the rotor processor with the 30/35beads and themorphine/lactose blend. After activating the rotor plate,set at 150 rpm, the PVP 5% w/w solution was sprayed onto the charge ofbeads and powder in a more aggressive manner. The inclusion of theMS/lactose blend along with the charge of 30/35 beads (12.6 kg) is doneto eliminate twinning of the substrate beads. Because the starting beadsare so small, the presence of minimal binding solution can causeagglomeration and batch failure. MS/lactose blend present with thesubstrate beads allows for preferential adhesion of the powder to thesubstrate beads versus bead to bead adhesion (a physical barrier to beadto bead surface). Once the 5 kg of powder blend is layered, powderfeeders were activated and the process was completed when all powderblend was layered, while the PVP solution was being sprayed.

EXAMPLES 4–5 Extended Release Low-Load Bead Formulation

In Examples 4–5, an extended release coating was applied to morphinesulfate beads prepared identically to those of Examples 1 and 2. Theformula for the functional coating of Examples 4 and 5 is set forth inTable 5 below:

TABLE 5 Example 4 Example 5 Ingredient (mg) % (mg) % Morphine Base Beads189.5 mg 86.7% 189.5 mg 83.0% Retardant Coating Eudragit RS 30D 9.5 mg*4.3% 15.2 mg* 6.7% Triethyl Citrate 1.9 mg 0.9% 3.0 mg 1.3% Talc 3.8 mg1.7% 6.1 mg 2.7% Purified Water qs — — — Overcoat Morphine Sulfate 3.0mg 1.4% 3.0 mg 1.3% Powder Opadry Red 10.8 mg 5.0% 11.4 mg 5.0%YS-1-1841 Purified Water qs — — — Total 218.45 mg 100.0% 228.2 mg 100.0%*Based on 27 mg MS5H₂O Equivalent of Immediate Release Beads of Example1

The extended release coating is manufactured as follows:

The Eudragit RS 30D is plasticized with triethyl citrate and talc forapproximately 30 minutes. A load of the morphine sulfate beads ischarged into a Wurster Insert of a Glatt equipped with a 1.2 mm spraynozzle and the beads are coated to a weight gain of 5% and 8%,respectively. The final protective Opadry dispersion overcoat is thenapplied in the Wurster Insert. Upon completion the beads are cured fortwo days in a dry oven of 45° C. The cured beads were then filled intogelatin capsules at a 30 mg strength. Dissolution testing were conductedon the gelatin capsules. via U.S.P. Apparatus II (Paddle Method). Thecapsules were placed into 700 ml of simulated gastric fluid (withoutenzymes) for the first hour at 100 rpm and 37° C., and then in the samevessel 200 ml of phosphate buffer was added to make 900 ml of simulatedgastric fluid (without enzymes) after the first hour. The results of thepercent of morphine sulfate dissolved in relation to time, are set forthin Table 6 below:

TABLE 6 Percent Morphine Sulfate Dissolved Time Example 4 Example 5 1hour 11.9% 10.2% 2 hours 15.4% 11.3% 4 hours 28.1% 12.8% 8 hours 58.3%16.4% 12 hours 79.2% 29.6% 18 hours 92.0% 58.1% 24 hours 96.6% 73.2%

A bioavailability study was conducted with Examples 4 and 5 dosedonce-a-day, using the commercially available product MS Contin® which isdesigned for twice daily dosing. Examples 4 and 5 are designed for oncedaily dosing. The results are provided in Table 7 below, and aregraphically depicted in FIG. 2:

TABLE 7 Example AUC T_(max) C_(max) MS Contin ® 99 2.2 13.0 Example 4 -Fasted 107 5.9 5.4 Example 4 - Fed 116 6.9 5.9 Example 5 - Fasted 13615.0 3.9

From the above data it can be seen that the formulation of Example 4 isan ideal for a once-a-day product without a food effect. Example 5 wouldbe for dosing for at least once-a-day or substantially longer.

EXAMPLE 6

Beads with a high-load of morphine sulfate were produced with the use ofa powder layering technique in the Glatt Rotor Processor. Lactose wasblended with the morphine sulfate prior to manufacture. The manufacturewas otherwise the same as in Example 2 above. The formulation of thehigh load beads is set forth in Table 8 below:

TABLE 8 High-Load Beads Percent Ingredient mg/unit (%) Morphine SulfatePowder 30.0 mg 63.3% Lactose Hydrous Impalpable 6.0 mg 12.7% PovidoneC-30 1.25 mg 2.6% Sugar Beads 7.75 mg 16.4% Opadry 2.37 mg 5.0% PurifiedWater qs — Total 47.37 mg 100.0%

The sustained release coating comprises a mixture of acrylic polymers(i.e., Eudragit® RS and RL). A hydroxypropylmethylcellulose (HPMC)protective coat is also included between the Eudragit layer and themorphine immediate release layer to further enhance stability. Theformula of the sustained release coating of Example 6 is set forth inTable 9 below:

TABLE 9 Amt/Unit Ingredient (mg) Percent (%) Morphine (high load) basebeads 42.63 mg 78.8% Retardant Coating Eudragit RS 30D 2.1 mg 3.9%Eudragit RL 30D 0.05 mg 0.1% Triethyl Citrate 0.45 mg 0.8% Talc 0.85 mg1.6% Overcoatings Opadry Blue YS-1-10542A 2.45 mg 4.5% Purified Water qs— Morphine Sulfate Powder 3.0 mg 5.5% Opadry Blue YS-1-10542A 2.55 mg4.8% Purified Water qs — Total 54.08 mg 100.0%

The extended release coating and the immediate release overcoat wereapplied as follows. The Eudragit RL 30D is plasticized with triethylcitrate and talc for approximately 30 minutes. A load of the morphinesulfate beads is charged into a Wurster Insert of a Glatt equipped witha 1.2 mm spray nozzle and the beads are coated to a weight gain of 5%.The final protective Opadry dispersion overcoat is then applied in theWurster Insert. Upon completion the beads are cured for two days in adry oven of 45° C. The cured beads were then filled into gelatincapsules at a 30 mg strength. The cured beads were then filled intogelatin capsules at a strength of 30 mg.

The capsules were then subjected to dissolution testing. Dissolutiontesting was conducted on the finished products via USP ApparatusII-(Paddle Method). The capsules were placed into 700 ml of simulatedgastric fluid (without enzymes) for the first hour at 100 rpm and 37°C., and then in the same vessel 200 ml of phosphate buffer is added tomake 900 ml of simulated gastric fluid (without enzymes). The results ofdissolution testing are set forth in Table 10 below:

TABLE 10 Percent Morphine Time Sulfate Dissolved 1 hour 11.7% 2 hours12.1% 4 hours 22.0% 8 hours 45.3% 12 hours 63.7% 18 hours 81.8% 24 hours92.5%

The dissolution testing as set forth in Table 10 indicates that thisproduct would be suitable for once-a-day administration.

A human single dose bioavailability study was then conducted using areference standard (MS Contin®), which is approved for twice-a-dayadministration and the formulation of Example 6, which were designed foronce-a-day administration. The in-vivo results are summarized in Table11 below.

TABLE 11 Group AUC C_(max) (ng/ml) T_(max) (Hours) MS Contin Tablets 11411.6 2.8 Example 6 141 4.0 12.9

The above data show that Example 6 is suitable for once-a-dayadministration.

COMPARATIVE EXAMPLE 7 Morphine Sulfate High-Load Multidose Beads

A batch of morphine sulfate high-load beads was manufactured using theprocess of powder layering on the rotor processor of the Versa Glatt.The formula made is as follows:

TABLE 12 Ingredient Amt/Unit (mg) Morphine Sulfate H₂O Powder 30 mgPovidone 1.25 mg Sugar Beads 25/30 7.75 mg Purified Water — Opadry Blue(YS-1-10542A) 2.05 mg Total 41.05 mg

Povidone was dissolved in water to yield a 5% w/w solution. Next, OpadryBlue was dissolved in water to yield a 15% w/w dispersion for finalfilmcoating. The rotor processor was charged with the 25/30 sugar beads,and the powder was then added onto the beads via a powder feeder and thebinder solution was simultaneously sprayed on the beads while they arerotating in the Glatt rotor processor. The beads produced wererelatively soft.

A final protective overcoat of the Opadry blue was then applied in therotor processor.

The beads were then overcoated with a controlled release functionalcoating with the following:

TABLE 13 Ingredient Amt/Unit Amt/Batch Morphine Sulfate High-load Beads40.05 mg 600.0 g Opadry Blue YS-1-10542A 1.35 mg 20.2 mg Purified Water— qs Eudragit RS30D 1.65 mg 24.7 g Triethyl Citrate 0.35 mg 5.2 gPurified Water — qs Opadry Blue YS-1-10542A 2.3 mg 34.5 g Purified Water— qs Total 46.35 mg 694.3 g

The batch was processed in the Wurster insert of the versa glatt andcured at 45° C. dry for two days and dissolution for this batch is asfollows:

TABLE 14 Time (hr) % Dissolved 1 4.6 2 6.9 4 25.6 8 58.7 12 78.7 18 94.724 102.4

The beads produced had unsatisfactory friability, were fragile and aninordinate amount of fine particles when a coating was applied to thebeads.

EXAMPLE 8

A batch of morphine sulfate high-load beads was manufactured using analternate method of powder layering. The formula is as follows:

TABLE 15 Ingredient Amt/Unit Morphine Sulfate Powder 54.0 mg LactoseHydrous Impalpable 10.8 mg Povidone 2.25 mg Sugar Beads 30/35 50.1 mgPurified Water — Opadry Blue YS-1-10542A 6.1 mg Total 123.25 mg

The high-load beads were prepared by first blending the morphine sulfatepowder with the lactose hydrous imp. After blending, the Glatt rotorprocessor was charged with the sugar beads and 5 kg of morphinesulfate/lactose blend. The rotor processor was then activated, and thePVP 5% solution was sprayed into the batch. The 5 kg of morphinesulfate/lactose blend is layered without agglomeration occurring. Usingthis procedure, the PVP solution spray rate can be increasedaggressively as compared to the method employed in other methods. Oncethe 5 kg of powder blend is layered, powder feeders were activated andthe process was completed when all powder blend was layered, while thePVP solution was being sprayed.

EXAMPLE 9

In Example 9, the low-load morphine sulfate beads were manufactured inthe same manner as outlined in Example 1. The formula was as follows:

TABLE 16 Ingredient Amt/Unit (mg) Percent (%) Morphine Sulfate Powder30.0 mg 14.3 Lactose Hydrous Impalpable 42.5 mg 20.2 PVP 2.5 mg 1.2Sugar Beads 18/20 125.0 mg 59.4 Purified Water qs — Opadry Red YS-1-184110.5 mg 4.9 Total 210.5 mg 100.0%

A sustained release coating of ethylcellulose with 5% HPMC as poreformer was then applied. A commercial product which is an ethylcellulosedispersion known as Aquacoat® was used.

The sustained release coating was manufactured as follows:

The pore former Methocel E5 Premium (HPMC), was dispersed and dissolvedin enough purified water to yield a 2% w/w solution.

An Aquacoat dispersion was plasticized with triethyl citrate forapproximately 30 minutes. After 30 minutes the HPMC dispersion was mixedinto the plasticized Aquacoat dispersion, and blended for an additional15–30 minutes. A load of the morphine sulfate beads was charged into aUniglatt Wurster Insert equipped with a 1.2 mm fluid nozzle. The beadswere then film coated with the Aquacoat/HPMC dispersion (in a ratio of95:5) to a weight gain of 5%.

The controlled release coating formula used in Example 9 is set forth inTable below:

TABLE 17 Ingredient Amt/Unit Morphine Sulfate Base Beads 210.5 mgAquacoat ECD 30 (solids) 10.0 mg Methocel E5 Premium 0.5 mg TriethylCitrate 2.1 mg Purified Water qs Opadry Red YS-1-1841 11.7 mg PurifiedWater qs Total 234.8 mg

After completion of the application of the sustained release coatingprocess, the coated beads were discharged from the Wurster Insert into acuring tray and cured in a temperature/humidity chamber at 60° C./80% RHfor 72 hours. Upon completion of this curing step, the beads were driedto a LOD of 4% or less and were given a final overcoat of Opadry RedYS-1-1841 (15% w/w solution) using the Uniglatt Wurster Insert. Thebeads were then filled into hard gelatin capsules using a capsulefilling machine to obtain the finished product.

The finished product was then subjected to dissolution testing via USPApparatus II (paddle method), 100 rpm, 37° C., 700 ml simulated gastricfluid (without enzyme) for one hour, and then 900 ml simulated gastricfluid (without enzymes after first hour).

The results are as follows:

TABLE 18 Time (hours) % Morphine Dissolved 1 16.9 2 29.6 6 52.3 8 79.812 92.8 18 101.4 24 104.7

EXAMPLE 10

In Example 10, morphine sulfate controlled release beads with acontrolled release coating of 5% w/w (including 3% HPMC as a poreformer, by weight of the coating), were prepared.

Morphine sulfate controlled release beads was manufactured with a 5% w/wcontrolled release coating and a 5% HPMC overcoat. The morphine sulfatebase beads to which the controlled release coating was applied areprepared as described in Example 9. Thereafter, the controlled releasecoating was prepared and applied to the beads to a weight gain of 5%.Further information concerning the formulation of Example 10 is providedin Table 19 below:

TABLE 19 Ingredient Amt/Unit Morphine Sulfate Base Beads 210.5 mgAquacoat ECD 30 (solids) 10.2 mg Methocel E5 Premium 0.3 mg TriethylCitrate 2.1 mg Purified Water qs Opadry Red YS-1-1841 11.7 mg PurifiedWater qs Total 234.8 mg

The manufacturing process and curing and encapsulation technique usedwas the same for Example 10 as per Example 9, the difference being thatthe beads were filmcoated with an Aquacoat/HPMC (97:3) dispersion inExample 10.

The results of dissolution testing conducted in the same manner as perExample 21 are set forth in Table 20 below:

TABLE 20 Time (hours) % Morphine Dissolved 1 17.8 2 28.4 4 46.7 8 73.1 186.0 2 99.0

A human bioavailability study was then conducted with the capsulesproduced in Examples 9 and 10 using MS Contin as the reference. Examples9 and 10 were designed for once daily dosing. In this study the effectof food was also investigated. Table 21 provides a summary of theresults obtained.

TABLE 21 Study Group AUC T_(max) C_(max) Ex. 9 (95:5 Fasted) 93 3.6 7.0Ex. 10 (97:3 Fasted) 101 5.6 5.9 Ex. 10 (97:3 Fed) 96 7.8 5.9 MS Contin(Fasted) 103 2.3 13.0

The bioavailability of Example 10 is graphically depicted in FIG. 3,showing that there is no food effect.

EXAMPLE 11 Immediate Release Low-Load Codeine Bead Formulation

In this example, a low-load bead formulation is prepared using a powderlayering technique in a Glatt Rotor Processor. Following the procedureof Example 1, the beads are prepared by spraying the aqueous bindersolution onto the beads 18/20 mesh to provide the beads with a tackysurface. Thereafter, a powder consisting of a homogeneous mixture ofcodeine phosphate USP powder and hydrous lactose impalpable powder issprayed onto the beads after the beads have become tacky. The beads arethen dried and sieved to obtain a powder-layered multiparticulateproduct having a suitable range of particle size. The formula of thecodeine phosphate USP powder beads is set forth in Table 22 below:

TABLE 22 Amt/Unit Ingredient (mg) Percent (%) Codeine Phosphate USPSpecial Powder 30.0 mg 14.3% Lactose Hydrous Impal 42.5 mg 20.2% PVP 2.5mg  1.2% Sugar Beads 18/20 125.0 mg 59.4% Purified Water qs — Opadry RedYS-1-1841 10.5 mg  4.9% Total 210.5 mg 100.0% 

The lactose hydrous impalpable which is used has a bulk density of 0.56g/ml and a tapped bulk density of about 0.64 g/ml. The codeine phosphateUSP special powder has a bulk density of about 0.55 g/ml. Aftercompletion of the powder-layering, the beads are filled into gelatincapsules at a 30 mg codeine strength.

EXAMPLE 12–15 Immediate Release Low-Load Bead Formulations

In these examples, further low-load bead formulations are prepared usingthe same powder layering technique described in Example 11 using a GlattRotor Processor are undertaken. The lactose hydrous impalpable used hasa bulk density of 0.56 g/ml and a tapped bulk density of about 0.64g/ml.

Example 12: acetaminophen-bulk density of about 0.42 g/ml.

Example 13: metoclopramide HCl-bulk density of about 0.5 g/ml.

Example 14: codeine sulfate USP medium crystals-fine-bulk density ofabout 0.6 g/ml.

Example 15: tramadol HCl-bulk density of about 0.42 g/ml.

In each example, after completion of the powder-layering, the beads arefilled into gelatin capsules.

EXAMPLES 16–17 Extended Release Low-Load Bead Formulation

In these examples, the techniques of Examples 4–5 are repeated toprovide an extended release coating to the codeine phosphate USP specialpowder beads prepared in Example 11. The formula for the coatings ofExamples 16 and 17 are set forth in Table 23 below:

TABLE 23 Example 16 Example 17 (mg) % (mg) % Ingredient Codeine 189.5 mg86.7% 189.5 mg 83.0% Phosphate USP Special Powder Beads RetardantCoating Eudragit 9.5 mg*  4.3% 15.2 mg*  6.7% RS 30D Triethyl Citrate1.9 mg  0.9% 3.0 mg  1.3% Talc 3.8 mg  1.7% 6.1 mg  2.7% Purified Waterqs — — — Overcoat Codeine 3.0 mg  1.4% 3.0 mg  1.3% Phosphate USPSpecial Powder Beads Opadry Red 10.8 mg  5.0% 11.4 mg  5.0% YS-1-1841Purified Water qs — — — Total 218.45 mg 100.0%  228.2 mg 100.0% The extended release coating is manufactured as follows:The Eudragit RS 30D is plasticized with triethyl citrate and talc forapproximately 30 minutes. A load of the codeine phosphate USP specialpowder beads is charged into a Wurster Insert of a Glatt equipped with a1.2 mm spray nozzle and the beads are coated to a weight gain of 5% and8%, respectively. The final protective Opadry dispersion overcoat isthen applied in the Wurster Insert. Upon completion the beads are curedfor two days in a dry oven of 45° C. The cured beads were then filledinto gelatin capsules at a 30 mg strength.

EXAMPLES 18–21 Comparison of Sprayed Dryed Lactose to Hydrous LactoseImpalpable

In these examples, the suitability of spray dried lactose was comparedto the suitability of hydrous lactose impalpable for powder layeringinert beads. The suitability of spray dried lactose was ascertainedaccording to the following experimental procedure:

Example 18 Example 19 Ingredients Amount/unit Amount/batch Lactose,Spray Dried  85 mg 425 mg Polyvinylpyrrolidone (PVP)  15 mg  75 mgNupariel 18/20 beads 200 mg 1000 mg  Deionized water Q.S.Procedurea) A Versa Glatt bowl was charged with 1 kg Nupariel 18/20 beads.b) The beads were powder layered with a blend of PVP and spray driedlactose while spraying deionized waterc) The beads were dried and discharged

It was surprisingly found that the powder-layered beads obtained throughthe use of spray-dried lactose as the processing aid (instead of hydrouslactose impalpable) did not produce a pharmaceutically acceptableproduct. In particular, the product which was obtained with spray-driedlactose had a rough surface and was irregular in shape. This irregularshape would not lend itself to be encapsulated. Nor would this irregularshape lend itself to being film-coated in a uniform manner, with respectto achieving a uniform thickness of functional film around thesubstrate. Further, due to the irregularity of the shape, thepowder-layered beads have a high angle of repose, and therefore wouldprovide poor filling characteristics on a conventional capsule fillingmachine. This would result in unacceptable fluctuations in the weight ofthe final encapsulated product.

In contrast, the suitability of hydrous lactose impalpable for powderlayering inert beads was ascertained according to the followingexperimental procedure:

Example 20 Example 21 Ingredients Amount/unit Amount/batch HydrousLactose Impalpable  85 mg  850 mg Polyvinylpyrrolidone (PVP)  15 mg  150mg Nupariel 18/20 beads 200 mg 2000 mg Deionized water Q.S.Procedurea) A Versa Glatt bowl was charged with 2 kg Nupariel 18/20 beads.b) The beads were powder layered with a blend of PVP and hydrous lactoseimpalpable while spraying deionized waterc) The beads were dried and discharged

In contrast to the powder layered beads obtained using spray driedlactose, the powder-layered beads produced using hydrous lactoseimpalpable as the processing aid had smooth surfaces and had excellentbinding and layering. The beads exhibited excellent capsule fillingcharacteristics which would not result in unacceptable fluctuations inthe weight of the final encapsulated product. The beads also provided anexcellent substrate for the application of a uniform film-coating.

The examples provided above are not meant to be exclusive. Many othervariations of the present invention would be obvious to those skilled inthe art, and are contemplated to be within the scope of the appendedclaims. For example, it is contemplated that other pharmaceuticallyacceptable salts or complexes of morphine may be used instead of part orall of the preferred morphine salt, morphine sulfate. Likewise, it iscontemplated that other pharmaceutically acceptable materials may beused to impart a sustained release to the morphine formulations of theinvention, e.g., to in a sustained release coating.

1. A method for preparing powder-layered beads containing atherapeutically effective agent, comprising powder-layering inert beadshaving a diameter from about 0.1 mm to about 2.5 mm with a homogeneouspowder mixture comprising a therapeutically active agent and aprocessing aid having a bulk density which is substantially similar tothe bulk density of the therapeutically effective agent, wherein saidprocessing aid is not microcrystalline cellulose, until said beadsachieve a weight gain of at least about 10% to about 100%.
 2. The methodof claim 1 wherein said processing aid is not water swellable.
 3. Themethod of claim 1 wherein said processing aid is hydrous lactoseimpalpable.
 4. The method of claim 1 wherein said processing aid ismaltodextrin.
 5. The method of claim 1 wherein said processing aid ispovidone.
 6. The method of claim 1 wherein said processing aid ispregelatinized corn starch.
 7. The method of claim 1 wherein saidprocessing aid is confectioner's sugar.
 8. The method of claim 1 whereinsaid processing aid is talc.
 9. The method of claim 1 wherein the bulkdensity of said processing aid is from about 75% to about 125% of thebulk density of said therapeutic agent.
 10. A method for preparing anoral dosage form of powder-layered beads containing a therapeuticallyeffective agent, comprising (A) identifying the bulk density of thetherapeutically effective agent to be powder-layered; (B) identifying aprocessing aid in the form of a powder having a bulk density which issubstantially similar to the bulk density of the theraeuticallyeffective agent, wherein said processing aid is not microcrystallinecellulose; (C) admixing the therapeutically effective agent with saidprocessing aid to form a homogeneous powder mixture; and (D)powder-layering inert beads having a diameter from about 0.1 mm to about2.5 mm with said homogeneous powder mixture until said beads achieve aweight gain of at least about 10% to about 100%.
 11. The method of claim10, further comprising spraying an aqueous binder solution onto saidinert beads prior to said powder-layering of step (D) in order toprovide said beads with a tacky surface.
 12. The method of claim 10,wherein said therapeutically active agent and said processing aid eachhave a bulk density from about 0.2 to about 0.9 g/ml.
 13. The method ofclaim 10, wherein the bulk density of said processing aid is from about75% to about 125% of the bulk density of said therapeutic agent.
 14. Themethod of claim 10, wherein said processing aid is not water swellable.15. A method for preparing an oral dosage form of powder-layered beadscontaining a therapeutically effective agent having a bulk density fromabout 0.2 to about 0.8 g/ml, comprising (A) identifying the bulk densityof the therapeutically effective agent to be powder-layered; (B)identifying a processing aid in the form of a powder having a bulkdensity from about 0.4 to about 0.9 g/ml which is substantially similarto the bulk density of the therapeutically effective agent, wherein saidprocessing aid is not microcrystalline cellulose; (C) admixing thetherapeutically effective agent with said processing aid to form ahomogeneous powder mixture; and (D) powder-layering inert beads having adiameter from about 0.1 mm to about 2.5 mm with said homogeneous powdermixture until said beads achieve a weight gain of at least about 10% toabout 100%.
 16. The method of claim 15 wherein the bulk density of saidprocessing aid is from about 75% to about 125% of the bulk density ofsaid therapeutic agent.
 17. The method of claim 15 wherein saidprocessing aid is not water swellable.